DESCRIPTION: The proposed work is based on the hypothesis that cytotoxic actions of activated microglia, reacting to neuritic and core senile plaques, contribute to the neuronal injury associated with Alzheimer's disease (AD). The PI has recently demonstrated that a neurotoxic amine can be extracted from AD brain which is not present in control, aged brains. This toxin is distinct from Beta-amyloid, but is similar in properties to a toxin secreted by plaque-activated microglia in tissue culture. Recent work has also shown that mature plaques in AD brain are invariably associated with microglia that show signs of activation. Preliminary data indicate that Beta-amyloid peptide 1-42 (ABeta1-42) found in senile plaques provides a signal to elicit release of microglial cytotoxins. The interaction between ABeta1-42 and microglia is the focus of the proposed work. The PI has developed strong evidence showing that while ABeta1-42, the primary protein component of plaques, is the most potent activator of microglia, truncated versions of peptide suggest the existence of two distinct domains, a cell binding domain and an intracellular activating domain. The PI will delineate these ABeta domains by study of specific peptide fragments and by selective chemical and enzymatic modifications of specific amino acid residues. Endpoints will include cell binding assays and neuron killing assays to distinguish between binding and activating regions within ABeta. The PI will also examine the role of plaque-associated chaperon molecules which appear to influence the way in which ABeta activates microglia. Particular effort will examine the effects of glycosaminoglycans and the isoforms of apolipoproteins. Finally, the PI will explore strategies to block ABeta and native plaque induction of neurotoxic microglia using competition with cell binding domains and select chemical modification of ABeta activating domains. The plaque-microglia interactions described here appear to be singular to AD pathology and provide a unique opportunity to delineate specific signals that elicit neuronal injury and to develop selective therapeutic strategies.